A. Field of the Invention
The invention relates to methods and compositions for treating cancer, particularly solid tumor cancers. Methods and compositions include capsazepine (CPZ), that is, 2-[2-(4-chlorphenyl)ethylamino-thiocarbonyl]-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-2-benzazepine, CPZ analogs, or other antagonists of TRP (transient receptor potential) channel Vanilloid subtype 1 (TRPV1, also known as “transient receptor potential cation channel, subfamily V, member 1”).
B. Description of Related Art
CPZ has been characterized as a competitive antagonist of both capsaicin (CAP) and the CAP-related compound resiniferatoxin (RTX) [Bevan S., Hothi S. et al. (1992; “Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin,” Br. J. Pharmacol. 107: 544-552)]. CAP and RTX are TRPV1 agonists, but CPZ blocks the activation by chemicals of the TRPV1 channel. In mammals, the TRPV1 channel functions as a pain and temperature sensor.
Numerous patent documents disclose CAP derivatives and their use in treating pain. For example, U.S. Pat. No. 5,403,868 [“Capsaicin derivatives”] discloses compounds having “in particular analgesic and anti-inflammatory” utility. Similarly, published U.S. Patent Publication No. 20060035939 [“3-aminobenzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity”] and U.S. Pat. No. 7,906,508 [“3,4-dihydrobenzoxazine compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity”] disclose “treating diseases involved in VR1 activity such as pain, acute pain, chronic pain, neuropathic pain, rheumatoid arthritis pain, and neuralgia.” Also, U.S. Pat. No. 7,514,562 [“Urea derivatives and their use as vanilloid receptor antagonists in the treatment of pain”] discloses testing vanilloid receptor antagonists for countering paw hyperalgesia in guinea pig. As a further example, U.S. Pat. No. 8,008,292 [“Condensed benzamide compounds and inhibitors of vanilloid receptor subtype 1 (VR1) activity”] discloses multiple compounds that alleviate pain and that resemble known vanilloid receptor subtype 1 (VR1) antagonist. Each patent document or other reference noted in this application is herein incorporated by reference in its entirety.
To various degrees, many of the compounds disclosed in these patent documents structurally resemble CPZ, the structure of which may be diagrammed as follows:

The disclosure herein relates to composition comprising CPZ or an analog of CPZ, and, in particular, the disclosure herein relates to the novel and nonobvious use of a composition comprising CPZ or an analog of CPZ in treating cancerous cell growth, particularly of a solid tumor cancer, in a subject.
Different types of solid tumors are named for the types of cells that form these tumors. Examples of types of solid tumor cancers include lymphomas (formed from lymphocytes), sarcomas (formed from cells of mesenchymal origin such as bone, cartilage, or muscle), and carcinomas (formed from cells of epithelial origin such as breast, colon, or lung).
Oral squamous cell carcinoma (OSCC) is the eighth most common cancer in the United States. Furthermore, OSCC is an extremely aggressive cancer that kills 50% of patients within five years of their initial diagnosis. While advances in local regional control have improved the overall survival for early disease stages 1 and 2, the death rate has not improved significantly in 40 years (American Cancer Society, Cancer Facts and Figures 2012). This is due primarily to the development of local recurrences and metastatic expansion that impinges upon critical structures thereby disallowing surgical resection. Importantly, as tumor burden increases and surgical resection is not possible, OSCC patients suffer immeasurable pain. Therefore, there is a great need to develop a means of reducing tumor volume to allow for either surgical resection or a prolonging of life expectancy for this patient population, or to assist in palliative care—both during treatment and for patients at the end of life.
TRP channels have been well-characterized in neurons where their functions are defined by induction of nociception in response to a noxious stimulus. However their expression and function in non-neuronal tissues, particularly in the context of malignant transformation, yet remain not well understood. Several authors have reported changes in expression of TRP channels in multiple tumor types (Prevarskaya, et al., 2007). TRPM1 has decreased expression in melanoma (Duncan, et al., 1998; Fang & Setaluri, 2000; Deeds, et al., 2000; Duncan, et al., 2001); TRPM8 has increased expression in prostate, breast, lung, colon, pancreatic cancers and melanoma (Tsavaler, et al., 2001; Fuessel, et al., 2003; Prevarskaya, et al., 2007; Mergler, et al., 2007); TRPV1 shows increased expression in prostate, colon and pancreatic cancers, but TRPV1 shows decreased expression as bladder cancer progresses (Domotor, et al., 2005; Hartel, et al., 2006; Lazzeri, et al., 2005; Sanchez, et al., 2005); and TRPV6 shows increased expression in prostate, breast, thyroid, colon, and ovarian cancers (Fixemer, et al., 2003; Zhuang, et al., 2002; Wissenbach, et al., 2004; Peng, et al., 2001; Peng, et al., 2000).
These findings have indicated that TRP channels might be useful as therapeutic targets for treating cancers. For example, it is hypothesized that treatment of tumors with TRP channel agonists, specific for tumor type, could result in a large influx of calcium (Ca++) thereby inducing apoptosis (Prevarskaya, et al., 2007). Reilly and colleagues demonstrated that treatment with the TRPV1 agonist CAP did result in apoptosis in cultured cells of an immortalized human bronchiolar epithelial cell line transformed with a TRPV1 insert to overexpress TRPV1 (Reilly, et al., 2003). However, a peculiar finding was seen in that the TRPV1 antagonist CPZ failed to reverse these effects. Curiously, CPZ appeared to be more effective at inducing apoptosis in these immortalized cultured cells than CAP (Reilly, et al., 2003). The authors conjectured that TRP channels often function in heteromeric tetramers with other TRP channels and perhaps this heteromeric interaction was not taking place within the cell lines tested.
Another separate study evaluated the effects of CAP on liver cancer cells. This study aimed to activate the TRPV1 channel and induce a high influx of calcium into the cells so as to trigger cell death (Reilly, et al., 2003). Investigators pretreated the cells with CPZ and noted that it failed to reverse the effects of CAP. The authors argued that TRPV1 also interacts with TRPA1 and conjectured that interaction with TRPA1 may be the reason why CPZ failed to reverse the effects of CAP. These and other studies again simply support the assessment that the expression and function of TRP channels like TRPV1 in non-neuronal tissues, particularly in the context of malignant transformation, yet remain not well understood.